The cytochrome P450 3A subfamily is comprised of three genes, CYP3A4, CYP3A5, and CYP3A7; with CYP3A4 expressed in a majority of adult livers. Recently, CYP3A4 has also been identified in entercytes. Thus, intestinal CYP3A may play an important role in the oral bioavailability of CYP3A substrates such as midazolam, nifedipine, and cyclosporine. Midazolam is a 1,4-imidazobenzodiazepine that exhibits a lower that expected oral bioavailability assuming that the liver is the sole organ of metabolism. A goal of this study is to determine the contribution of intestinal cytochrome P450 3A to the observed overall bioavailability and systemic clearance of midazolam following stimultaneous intravenous and oral administration of midazolam and stable isotope (15N-midazolam). The liver and kidney are traditionally considered the major organs responsible for clearance of drug. Measurement of drug concentrations in portal venous blood, via portal vein catheter, is unique and will permit these investigators, for the first time, to directly ascertain whether the intestine is an important organ for systemic drug elimination.
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